Compounds of metalloids with nucleotides and their decomposition products



Patented Oct. 20, 1936 UNITED "STATES PATENT OFFICES COMPOUNDS METALLOIDS WITH NU- CLEOTIDES AND THEIR DECOLIPOSITION PRODUCTS Simon L. Ruskin, New York, N. Y assig'nor to Frances R. Ruskin, New York, N. Y.

No Drawing. Application November 2, 1933,

1 Serial No. 696,389

5 Claims. (01. 2609) contain a. pyrimidine ring in their molecule; it

is a continuation in part of my copending application Serial #650,137, filed January 4, 1933.

One object of this invention is to provide a method for producing metalloid compounds of isolated nucleotides or their isolated organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom.

Another object of this invention is the preparation of soluble compounds of metalloids' and non-metals with nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or.

the purine and pyrimidine bases derived therefrom, which compoundsare soluble in water or physiological salt solutions and contain a high percentage of said metalloids and non-metals.

Still another object of my invention is the preparation of soluble compounds of arsenic with nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the' nucleosides, or the purine and pyrimidine bases derived therefrom, which compounds are soluble in water or physiological salt solutions and contain a high percentage of arsenic.

A further object of my invention is the preparation of soluble compounds of antimony with pucleotides'or their organic hydrolytic decom- --f'position products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom. which compounds are soluble in water or physiological salt with nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom, which compounds are soluble in water or physiological salt solutions and contains, high percentage of halogens.

I A further object of this invention is the preparation of soluble compounds of selenium with nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom, which compounds are soluble .in water or physiological salt solutions and contain a high percentage of selenium. v

Other objects of this invention are to combine other non-metals, such as. sulfur, tellurium, phosphorus, silicon, boron and the like with nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom, which compounds are soluble in water or physiological salt solutions and contain a high percentage of said nonmetals. I

Under the expression nucleotides I include their organic hydrolytic decomposition products which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom and also compounds which are obtained from nucleoproteins by hydrolysis. The nucleotides are composed of nucleosides and phosphoric acid and are acids; they are decomposed by the action of hot water, ferments, acids or'alkalies. Some mononucleotides were isolated from pancreas and from extract of meat.

The nucleosides which, in combination with phosphoric acid, form the nucleotides, are glucosides of various purine and pyrimidine bases, 1'. e., compounds composed of carbohydrates and these bases.

pyrimidine bases, of which the following may -be mentioned: thymin, cytosin,'uracil, adenin and guanin. These final hydrolytic decomposition products, of course, have also been produced directly from nucleoproteins, nucleine and nucleotides by the action of acids or alkalies.

As the chemical constitution and the nomenof this invention are still in a state of considerable confusion, the following table is intended They are obtained by the action. of ferments upon said nucleotides and are finally decomposed into the various purine and clature of the compounds comprising the object to give a clearer picture of the scope of the invention and the relationship existing between all these compounds.

Itucleoprotein Albumen Albumen Nucleic acids of higher order True nucleic acid Dinu eotides Mononucleotides ,(e. g., 1ilidcnyziczs,

.- acids) Phosphoric acid Nucleosides (Glucosides) Pyrimidine derivatives gang thysin, ura cll) Carbohydrates (hexoses, pentoses) Purine derlvatives (e. g., guanin, xenthiii finhypo-d xan a enin) For the purpose of disclosing my invention 1 will describe the preparation of the combination of iodine with a mononucleotide (guanylic acid), of arsenic with adenin, of antimony with -a mixture of nucleotides and of selenium with adenosin (adeninriboside) without, however, limiting myself to these products.

Example 1 10 grams of finely pulverized guanylic acid are suspended in chloroform. An equimolecular amount of iodine dissolved in chloroform is slow- 1y added to this solution while: stirring vigorously and keeping the temperature below 25 C. -'After about V hour the reaction product is separated from the solvent and dried at about room temperature in a vacuum. The compound contains between 10 to 15% of iodine.

Instead of iodine, solutions of chlorine or bromine may be used. Or the reaction may be carried out by passing the halogen vapors overthe guanylic acid which is preferably arranged in thin layers or is kept in a rotating drum. The latter method is especially suitable for the preparation of chlorine and fluorine compounds.

Instead of using chloroform as solvent, other indifferent solvents may be used, such as benzene, toluene, xylene, carbontetrachloride andthe like. The reaction may also be carried out in aqueous solution or by treating the solutions ofmetal saltsor even the dry metal'salts of the nucleotides and their organic hydrolytic decomposition prod- Example 2 ized nucleotides or their organic hydrolytic decomposition products which contain a pyrimidine 'ring. Such arsenic compounds are soluble in water and alkalies. Arsenic compounds are also obtained by mixing aqueous'solutions of arsenic acid and nucleotides and precipitating by means of alcohol.

On combination of such arsenic nucleotide compounds with, for instance, heavy metals, such as gold, mercury, silver and the like, other valuable products are obtained which are superior to and less poisonous than the hitherto known and used arsenic compounds.

Erample A mixture of nucleotides comprising guanylic and adenylic acid as it is obtained by hydrolysis of nucleic acid with ammonia in an autoclave at 150 C. and repeated recrystallization, is ,dls-

solved in a salt solution, such as for instance.in a solution of sodium chloride. Hereto is added a solution of antimony trichloride in aqueous sodium chloride solution. The mixture is boiled and the antimony compound of the nucleotide is precipitated by the addition of hydrochloric acid. It forms easily soluble sodium salts which may be used for the treatment of infections caused by trypanosamae and spirochaetae, such as syphilis,

sleeping sickness andthe like.

Example 4 Adenosin (adenin riboside) in suspension in an inert solvent such as carbon tetrachloride is re-- acted.witlr selenotetrachloride while stirring vigorously and cooling to room temperature and the obtained chlorinated seleno-compound of adenosln is treated at rom temperature with diluted alkalies. 0n acidifying a compound is obtained which is easily soluble in alkalies and, although to a lesser degree, in water. Such a compound is of value in the treatment of neoplastic diseases and the like. Y

Likewise all the other not mentioned compounds of metallolds and non-metals may be produced, such as phosphorus, sulfur, tellurium, silicon, boron and the like compounds of nucleotides or their organic hydrolytic decomposition prod-.

ucts which contain a pyrimidine ring, such as the nucleosides, or the purine and pyrimidine bases derived therefrom.

The reaction conditions may be changed and also other variations may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

What I claim is:

1. As a therapeutic agent,the combination of an element of the group VB of the periodic system and a compound of the group consisting of isolated' nucleotides and their isolated decomposition products containing a pyrimidine ring.

2. As a therapeutic agent, the combination of an isolated nucleotide and arsenic.

3. As a therapeutic agent, the combination of an isolated nucleotide and antimony. I 5 4. As a therapeutic agent, the combination of an element of the group VB of the periodic system and an isolated nucleotide having a purine ring in its structure.

5. As a. therapeutic agent, the combination ofisolated adenylic acid and arsenic.

SIMON L. RUSKIN. 

